BRAF inhibitor receives FDA approval for metastatic, unresectable melanoma

The FDA announced today the approval of vemurafenib to treat BRAF V600E-positive metastatic or unresectable melanoma. Vemurafenib was reviewed under the FDA’s priority review program.

According to the agency, the BRAF inhibitor (Zelboraf, Genentech) has not been studied in patients whose melanoma tests negative for BRAF V600E by an FDA-approved diagnostic. The current approval comes in combination with the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic to help determine BRAF V600E status.

“This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival,” Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “In March, we approved Yervoy (ipilimumab, Bristol-Myers), another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”

Vemurafenib and the companion BRAF V600E test are being approved ahead of the drug’s Oct. 28, 2011 goal date and the companion diagnostics’ Nov. 12, 2011 goal date, according to the agency.

The safety and efficacy of vemurafenib, as well as the cobas diagnostic test, were established in a single international trial of 675 treatment-naïve patients with metastatic melanoma with the BRAF V600E mutation. Patients were assigned to vemurafenib or dacarbazine. The trial was designed to measure OS.

Patients assigned to vemurafenib have not reached median survival (77% still living), and median survival among those who received dacarbazine was 8 months (64% still living).

“Today’s approval of Zelboraf and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, said in the press release.

The most common adverse events associated with treatment were joint pain, rash, hair loss, fatigue, nausea and skin sensitivity when exposed to the sun. About 26% of patients developed cutaneous squamous cell carcinoma, which was managed with surgery. The FDA recommends that patients treated with vemurafenib should avoid sun exposure. The approval includes a medication guide to inform healthcare professionals and patients of the drug’s potential risks.

Sanjiv S. Agarwala, MD

The "holy grail" for cancer therapy (arguably) has been identifying a target and validating it with a drug that is effective against that target. For the approximately 50% of metastatic melanomas that harbor the BRAF mutation, this has been definitely achieved by vemurafenib with an impressive response rate, significant improvement in survival and a hazard ratio that has not been seen in melanoma studies prior to this trial. This is good news for patients suffering with this dreadful disease. Cancer cells are still smarter than us, so the next step is to find ways to abrogate the resistance that usually develops and to figure out how to combine targeted therapies with other effective modalities such as immunotherapy. A planned combination trial with vemurafenib and ipilimumab promises to be an exciting one.

– Sanjiv S. Agarwala, MD
HemOnc Today Editorial Board member

Vernon K. Sondak, MD

This latest FDA approval is tremendously significant. Since 1999 there had been no new treatments approved for melanoma, and now there have been three new drugs approved in one year.

To me and others treating this disease, perhaps the biggest significance is the promise that we have some really useful drugs to build on and to put together. These new drugs have different mechanisms of action and different strengths, and can be put together and other things can be brought in. The science is improving to the point where we can figure out why tumors are getting resistant to the drugs that we have and have a real hope of doing something about it.

So no one should think that this is it, and now we're finished taking care of melanoma patients and we can turn our attention to something else. Rather, this is the beginning of a new era of effective treatments. We have to build on those effective treatments and figure out how to combine them in increasingly more effective ways.

– Vernon K. Sondak, MD
HemOnc Today Editorial Board member

Allan C. Halpern, MD, MSc

This is a big step forward in melanoma therapy. For the significant percentage of patients with the disease who have this particular mutation, between 40% and 70%, it means there is now a highly active drug available.

In general, this is an exciting time in melanoma because Zelboraf comes on the heels of the approval of another important melanoma drug in March: Yervoy. That said, it remains likely that only a small percentage of treated patients will be cured of their disease. There's no question that the studies have shown a significant improvement in OS, but how durable that will prove to be, we're still waiting to learn.

– Alan C. Halpern, MD, MSc
Chief of Dermatology Service, Memorial Sloan-Kettering Cancer Center

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